The responsiveness of many cells to external chemical messengers, such as hormones, lymphokines, growth factors, neurotransmitters, and the like, is elicited by way of receptors to these substances. A large variety of these receptors are coupled with an enzyme system, adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cyclic AMP, or cAMP for short) and pyrophosphate. Cyclic AMP release inside a cell causes activation of other enzymes, resulting ultimately in the biological response. An important approach in the treatment of disease, or control of physiological states, is the ability to modify the responsiveness of cells to these messengers. By so doing, it may be possible to modify a number of conditions by a generic mechanism. In the discovery embodied within the invention disclosed and claimed herein, all cyclic AMP systems so far tested respond to silicate treatment.
It is estimated that 20 million people in the U.S. have osteoporosis, which results in 1.3 million fractures annually at a cost of $6.1 billion; Riggs, L. B. and Melton, L. J. III: Involutional Osteoporosis. N. Engl. J. Med. 26:1676-1684, 1986. The major contributing factors to osteoporosis is age-related bone mineral loss and estrogen deficiency due to natural menopause; Concensus Conference: Osteoporosis, JAMA 252:799-802, 1984; Avioli, L. V.: Osteoporosis: Pathogenesis and Therapy, in: Metabolic Bone Disease, Aviolo, L. V. and Krane, S. M. (eds), Academic Press, New York Vol I, pp 307-385, 1977. The mechanism by which this loss is incurred is unclear.
Cyclic AMP has been identified as a mediator of action of PTH as well as other hormones such as calcitonin on bone; Chase, L. R. and Aurbach, G. D.: The Effect of Parathyroid Hormone on The Concentrations of Adenosine 3",5"-Monophosphate In Skeletal Tissue in vitro, J. Biol. Chem. 245:1520-1526, 1970; Luben, R. A., Wong, G. L. and Cohn, D. V.: Biochemical Characterization with Parathormone and Calcitonin of Isolated Bone Cells: Provisional Identification Of Osteoclasts And Osteoblasts, Endocrinology 99:526-534, 1976; Peck, W. A., Burks, J. K., Wilkins, J., Rodan, S. B. and Rodan, G. A.: Evidence for Preferential Effects of Parathyroid Hormone, Calcitonin And Adenosine On Bone and Periosteum, Endocrinology 100:1357-1364, 1977; Rodan, G. A. and Martin, T. J.: Role of Osteoblasts In Hormonal Control Of Bone Resorption--A Hypothesis, Calcif. Tissue, Int., 33:349-351, 1981. The enzyme responsible for the generation of cyclic AMP, adenylate cyclase, is a protein complex consisting of three components: the hormone-specific receptor, the guanine nucleotide regulatory proteins (Ns and Ni), and the catalytic unit; Ross, E. M. and Gilman, A. G.: Biochemical Properties Of Hormone Sensitive Adenylate Cyclase, Annu. Rev. Biochem. 49:533-564, 1980. Stimulation of adenylate cyclase activity resulting from hormone binding to a specific receptor is brought about via activation of the stimulatory guanine nucleotide regulatory protein Ns; inhibition of adenylate cyclase activity resulting from activation of the inhibitory guanine nucleotide regulatory protein, Ni; Smigel, M., Katada, T., Northup, J. K., Bokoch, G. M., Ui, M. and Gilman, A.G.: Mechanism of Guanine Nucleotide-Mediated Regulation Of Adenylate Cyclase Activity, in: Advances in Cyclic Nucleotide and Protein Phosohorylation Research; Greengard, P. (ed) Raven Press, New York, 17:1-18, 1984; Cote, T. E., Frey, E. A. and Sekura, R. D.: Altered Activity Of The Inhibitory Guanyl Nucleotide-Binding Component (Ni) Induced By Pertussin Toxin, J. Biol. Chem. 259:8693-8698, 1984. The overall adenylate cyclase activity expressed in a given system seems to reflect the relative proportion of activated Ns and Ni present. The activation of the adenylate cyclase-cyclic AMP system involves the coordinated interaction of the structural components of the enzyme complex in the presence of guanine nucleotides and Mg.sup.++ ; Iyengar, R. and Birnbaumer, L.: Hysteric Activation Of Adenylyl Cyclases: I. Effect of Mg Ion On The Rate Of Activation By Guanine Nucleotides And Fluoride, J. Biol. Chem. 256:11036-11041. Most hormones have been shown to increase the magnesium affinity of adenylate cyclase; Iyengar, R. and Birnbaumer, L.: Hormone Receptor Modulates The Regulatory Component Of Adenylyl Cyclase By
Reducing Its Requirement For Mg.sup.++ And Enhancing Its Extent 0f Activation By Guanine Nucleotides, Proc. Natl. Acad. Sci. (USA) 79:5179-5183, 1982; Cech, S. V., Broaddus, W. C. and Maguire, M. E.: Adenylate Cyclase: The Role Of Magnesium And Other Divalent Cations, Mol. Cell. Biochem. 33:67-92, 1980, and it has been suggested that the mechanism of hormonal activation involves an increase in Mg.sup.++ affinity of the adenylate cyclase complex.
Calcium also has been shown to influence adenylate cyclase activity. Inhibition of adenylate cyclase by Ca.sup.++ at concentrations of 0.01-1.0 mM appears to be a general property of all adenylate cyclase enzymes; Cech, S. V., Broaddus, W. C. and Maguire, M. E.: Adenylate Cyclase: The Role Of Magnesium And Other Divalent Cations, Mol. Cell. Biochem. 33:67-92, 1980. A previous investigation of the effects of Ca.sup.++ on the adenylate cyclase activity in guinea pig bone revealed the presence of two calcium inhibition sites with calcium disassociation constants or approximately 1 micromole and 200 micromole; Rude, R. K.: Renal Cortical Adenylate Cyclase: Characterization Of Magnesium Activation, Endocrinology 113:1348-1355, 1983; Rude, R. K.: Skeletal Adenylate Cyclase: Effect Of Mg.sup.2+, Ca.sup.2+, and PTH, Calcif. Tissue. Int. 37:318-323, 1985. The high affinity calcium inhibition site is likely to play a physiological role in the regulation of bone adenylate cyclase.
Silicon has been demonstrated to be an essential trace element; Carlisle, E. M.: Silicon as an Essential Element, Fed. Proc. 33:1758-1766, 1974; Carlisle, E. M.: Silicon As An Essential Trace In Animal Nutrition, in: Silicon Biochemistry, Wiley, Chichester (Ciba Foundation Symposium 121), pp. 123-139, 1986. In biological tissues the highest levels of silicon are found in connective tissues. Silicon deficiency in the chick has been shown to impair normal skeletal development; Carlisle, E. M.: Silicon: An Essential Element For The Chick, Science, 178:619-621, 1972. Silicon appears to be necessary in areas of active bone growth and/or mineralization; Carlisle, E. M.: Silicon: An Essential Element for the chick, ibid.; Carlisle, E. M.: Silicon: A possible factor in bone calcification, Science, 167: 280, 1970. These effects are independent of vitamin D; Carlisle, E. M.: Silicon: A Requirement In Bone Formation Independent Of Vitamin D. Calcif. Tissue Int. 33:27-34, 1981.
Preliminary data from other investigators indicate that silicon compounds can increase bone mass. It has been proposed that silicon compounds may be beneficial in the treatment of osteoporosis; European Patent Application No. 86-116363.2.